Ischemia-Reperfusion Injury (IRI) is a complex pathophysiological process characterized by oxidative stress and inflammatory responses during tissue reperfusion, leading to severe organ dysfunction. Macrophages, as key immune cells, play a pivotal role in the pathogenesis of IRI, exhibiting dynamic functions that influence both tissue damage and repair. Despite extensive research, the precise mechanisms underlying macrophage-mediated IRI remain incompletely understood, necessitating a comprehensive review to explore their multifaceted roles and potential therapeutic targets.

This review aims to elucidate the diverse roles of macrophages in IRI, focusing on their involvement in programmed cell death mechanisms, communication with other immune cells, and regulatory effects on key organs affected by IRI. The review also explores potential therapeutic strategies targeting macrophages to mitigate IRI-induced injury. Key Scientific Concepts of Review: This article reviews the multifaceted roles of macrophages in IRI and explores various modes of macrophage programmed cell death induced by IRI, including gasdermin D-mediated pyroptosis, lipid peroxidation-associated ferroptosis, PARP-1-mediated PAR-dependent cell death, PANoptosis regulated by the PANoptosome, and the formation of macrophage extracellular traps (METs) induced by both reactive oxygen species-dependent and -independent pathways. Additionally, it discusses intercellular communication between macrophages and other immune cells in IRI, focusing on the bidirectional regulatory effects between macrophages and neutrophils, as well as their synergistic role in resolving inflammation. Moreover, the regulatory mechanisms of macrophages in IRI affecting key organs, such as the brain, lung, heart, kidneys and liver, have been systematically summarized. Finally, innovative therapeutic strategies targeting macrophages, including precise approaches such as regulating cell polarization, inhibiting excessive METs formation, and utilizing nano-drug delivery systems, are thoroughly analyzed. This review provides a significant theoretical foundation for clinical translational research on IRI.

Crush syndrome refers to the traumatic rhabdomyolysis leading to a spectrum of disorders culminating in acute kidney injury. The burden of crush syndrome is high, and mortality can be as high as 20%. The significant bulk of knowledge is from old articles. Over the last 10 years new research has occurred on diagnosis and treatment in animal models.

To overview of crush syndrome and discuss the newer advances related to the pathogenesis and management of a patient with crush syndrome.

The search of databases such as MEDLINE, Google Scholar, Web of Science, and EMBASE revealed 8226 articles. A thorough screening culminated in 83 crush syndrome articles included in this study.

Acute kidney injury in crush syndrome is currently thought to be due to iron retention. The management of crush syndrome has also been updated with antioxidants, and several gases are being used to treat crush syndrome. In the end, treatment of crush syndrome also includes mental, social, and physical rehabilitation for better outcomes.

The outcomes of crush syndrome have significantly improved with the introduction of newer treatment modalities, including antioxidants, hyperbaric oxygen therapy, and comprehensive mental, social, and physical rehabilitation.

Cellular prion protein (PrPC), known for its pathological isoform in prion diseases such as Creutzfeldt-Jakob disease, is primarily expressed in the nervous system but has also been detected in the blood and urine of individuals with renal dysfunction. However, the role of PrPC in the development of renal disease is unexplored. Here, we showed that PrPC was up-regulated in fibrotic renal lesions in biopsies from patients with chronic kidney disease (CKD), predominantly in proximal tubular epithelial cells (PTECs). Furthermore, renal expression of PrPC was positively correlated with the severity of renal failure and the decline in estimated glomerular filtration rate in patients with CKD. In mice, tubular-specific deletion of PrPC mitigated renal fibrosis induced by unilateral ureteral obstruction (UUO) or unilateral ischemia-reperfusion injury (UIRI). Mechanistically, PrPC was up-regulated by transforming growth factor-β1-suppressor of mothers against decapentaplegic 3 signaling. PrPC activated TANK binding kinase 1 (TBK1)-interferon regulatory factor 3 (IRF3) signaling through its capacity for liquid-liquid phase separation, which promoted a profibrotic response in PTECs and fibroblasts. Treating mice with amlexanox, a US Food and Drug Administration-approved inhibitor of TBK1, either before the onset of renal fibrosis (in UUO and UIRI models) or after its establishment (in adenine- and aristolochic acid-induced CKD models), mitigated worsening of renal fibrosis and renal function. Collectively, our findings uncovered a mechanism involving phase separation of PrPC underlying renal fibrosis and support further study of the PrPC-TBK1-IRF3 axis as a potential therapeutic target for CKD.

Macrophages are crucial to innate immunity, eliminating pathogens and damaged tissues through phagocytosis and modulating immune responses. Recently, macrophage extracellular traps (METs) have been identified as chromatin-based structures composed of DNA and various immune-related proteins. While METs play a defensive role in trapping and neutralizing pathogens, they are also implicated in disease pathology, contributing to chronic inflammation, tissue damage, and immune dysregulation. The precise mechanisms regulating MET formation are still under investigation, but emerging evidence indicates the involvement of various regulatory factors. Dysregulated MET activity has been associated with various diseases, including autoimmune disorders, cancer, and neurological conditions. A deeper understanding of MET mechanisms and their pathological impact may offer novel therapeutic strategies. Given the limited number of reviews and articles on METs, this review provides valuable insights into MET formation, regulatory pathways, and their role in disease progression.

Recent studies have highlighted the critical role of lipid metabolism in macrophages concerning lung inflammation. However, it remains unclear whether lipid metabolism is involved in macrophage extracellular traps (METs). We analyzed the GSE40885 dataset from the GEO database using weighted correlation network analysis (WGCNA) and further selection using the least absolute shrinkage and selection operator (LASSO) regression. We identified ABCA1, SLC44A2, and C3 as key genes jointly involved in lipid metabolism and METs. Additionally, immune infiltration analysis was performed using the Xcell and CIBERSORT algorithms, while single-cell transcriptome analysis was utilized using data from the Tabula Muris database. The expression of key genes was validated in external datasets (GSE42606, GSE27066, GSE137268, and GSE256534). Notably, our results indicated that ABCA1 expression was elevated in patients experiencing acute asthma exacerbations, which aligned with its expression trend in lipopolysaccharide (LPS)-induced macrophages. However, ABCA1 expression was reduced in cases of chronic and severe asthma. Results from immunofluorescence (IF), SYTOX Green staining, and Western blot analyses suggested that ABCA1 may play a role in the formation of METs both in vivo and in vitro. In conclusion, this study indicates that ABCA1 may be involved in METs. ABCA1 may represent a promising therapeutic target for asthma.

Acute kidney injury (AKI) involves the activation of intrarenal hemostatic and inflammatory pathways. Platelets rapidly migrate to affected sites of AKI and release extracellular vesicles (EVs) laden with bioactive mediators that regulate inflammation and hemostasis. While small interfering RNA (siRNA) is a potent gene-silencing tool for biomedical applications, its therapeutic application in vivo remains challenging. We developed an innovative nucleic acid delivery platform by hybridizing synthetic transformation-related protein 53 (p53) siRNA with autologous plasma and incubating the complex with autologous platelets. These engineered platelets selectively delivered p53 siRNA to injured renal tubular cells via EV-mediated cargo release, resulting in targeted p53 suppression in renal cells and subsequent attenuation of AKI progression. This platelet-centric translational strategy demonstrates significant potential for advancing precision therapies in AKI by exploiting endogenous platelet trafficking to deliver therapeutics directly to injury sites.

Urinary tract infections (UTIs) predominantly occur in the bladder and can potentially progress into life-threatening sepsis if uropathogens spread unconstrainedly into the bloodstream. Here, we identified a subset of suburothelial perivascular macrophages (suPVMs) in the bladder that exerted a pivotal barrier function to prevent systemic bacterial dissemination during acute cystitis. During the initial phase of uropathogenic Escherichia coli (UPEC) infection, suPVMs actively captured UPEC invading the laminal propria and maintained the integrity of inflamed vessels. They subsequently underwent METosis to expel macrophage extracellular DNA traps (METs) into the urothelium to sequester bacteria within this avascular compartment. Matrix metallopeptidase-13 was released along with METs to promote neutrophil transuroepithelial migration. Replenished suPVMs from monocytes following a prior infection were functionally competent to confer protection against recurrent UTIs. Our study thus uncovers a bladder-blood immune barrier in restraining uropathogen dissemination, which could have implications for the prevention and treatment of urosepsis.

A couple of S100 family proteins (S100s) have been reported to exert pro-inflammatory functions in the progression of renal fibrosis. Unlike some S100s which are expressed by both epithelial and stromal inflammatory cells, S100A7 is restricted expressed in epithelium. Persistent S100A7 expression occurs in some invasive carcinomas and is associated with poor prognostic factors. Whereas, whether it is implicated in renal tubular epithelial cell injury and kidney disease remains unexplored. In this study, we demonstrate that S100A7 is highly upregulated in tubular cells of both mouse renal fibrotic lesions and kidney biopsies from patients with chronic kidney disease (CKD). The level of renal S100A7 was associated with both the decline of renal function and the progression of renal fibrosis in CKD patients. Overexpressing S100A7a impaired fatty acid oxidation (FAO) and promoted lipid peroxidation in proximal tubular cells (PTCs). Mechanistically, S100A7a interacts with β-catenin, thereby preventing its ubiquitination and degradation by the β-TrCP-SCF complex, and in turn activated β-catenin signaling, downregulated the expression of PGC-1α. Additionally, S100A7a exacerbated lipid peroxidation via RAGE-p-ERK-NOX2 pathway. Specific deletion of S100a7a in tubular cells enhanced FAO and reduced lipid peroxidation, resulting in improved renal function and alleviation of renal fibrosis induced by unilateral ureteral obstruction and unilateral ischemia-reperfusion injury. Collectively, we delineate a previously unrecognized function of S100A7a in the progression of renal fibrosis.

The muscular system plays a critical role in the human body by governing skeletal movement, cardiovascular function, and the activities of digestive organs. Additionally, muscle tissues serve an endocrine function by secreting myogenic cytokines, thereby regulating metabolism throughout the entire body. Maintaining muscle function requires iron homeostasis. Recent studies suggest that disruptions in iron metabolism and ferroptosis, a form of iron-dependent cell death, are essential contributors to the progression of a wide range of muscle diseases and disorders, including sarcopenia, cardiomyopathy, and amyotrophic lateral sclerosis. Thus, a comprehensive overview of the mechanisms regulating iron metabolism and ferroptosis in these conditions is crucial for identifying potential therapeutic targets and developing new strategies for disease treatment and/or prevention. This review aims to summarize recent advances in understanding the molecular mechanisms underlying ferroptosis in the context of muscle injury, as well as associated muscle diseases and disorders. Moreover, we discuss potential targets within the ferroptosis pathway and possible strategies for managing muscle disorders. Finally, we shed new light on current limitations and future prospects for therapeutic interventions targeting ferroptosis.

Spleen tyrosine kinase (Syk), an important hub of immune signaling, is activated by several signalings in active lupus which could be interfered by Syk inhibitor but is still not completely evaluated in innate immune cells associated with lupus activity. Hence, a Syk inhibitor (fostamatinib; R788) was tested in vivo using Fc gamma receptor-deficient (FcγRIIb-/-) lupus mice and in vitro (macrophages and neutrophils). After 4 weeks of oral Syk inhibitor, 40 week-old FcγRIIb-/- mice (a full-blown lupus model) demonstrated less prominent lupus parameters (serum anti-dsDNA, proteinuria, and glomerulonephritis), systemic inflammation, as evaluated by serum TNFa, IL-6, and citrullinated histone H3 (CitH3), gut permeability defect, as indicated by serum FITC dextran assay, serum lipopolysaccharide (LPS), and serum (1 → 3)-β-D-glucan (BG), extracellular traps (ETs) and immune complex deposition in spleens and kidneys (immunofluorescent staining of CitH3 and immunoglobulin G) than FcγRIIb-/- mice with placebo. Due to the spontaneous elevation of LPS and BG in serum, LPS plus BG (LPS + BG) was used to activate macrophages and neutrophils. After LPS + BG stimulation, FcγRIIb-/- macrophages and neutrophils demonstrated predominant abundance of phosphorylated Syk (Western blotting), and the pro-inflammatory responses (CD86 flow cytometry analysis, supernatant cytokines, ETs immunofluorescent, and flow cytometry-based apoptosis). With RNA sequencing analysis and western blotting, the Syk-p38MAPK-dependent pathway was suggested as downregulating several inflammatory pathways in LPS + BG-activated FcγRIIb-/- macrophages and neutrophils. Although both inhibitors against Syk and p38MAPK attenuated macrophage and neutrophil inflammatory responses against LPS + WGP, the apoptosis inhibition by p38MAPK inhibitor was not observed. These results suggested that Syk inhibitor (fostamatinib) improved the severity of lupus caused by FcγRIIb defect partly through Syk-p38MAPK anti-inflammation that inhibited both ET formation and cytokine production from innate immune cells.

Perivascular adipose tissue (PVAT) regulates vascular tone and is composed of adipocytes and several leukocyte subpopulations. Diet can modify PVAT function, as obesogenic diets cause morphological changes to adipocytes and skew the leukocyte phenotype, leading to PVAT dysregulation and impaired vasoregulation. Of note, platelets, the clot-forming cells, also modulate many facets of leukocyte activity, such as tissue infiltration and polarity. We aimed to determine whether platelets regulate the leukocyte populations residing within PVAT. Male C57Bl/6J mice were fed a Western diet (30% kcal sucrose, 40% kcal fat, 8.0% sodium) to develop obesogenic conditions for PVAT leukocyte remodeling. Diet was either administered acutely (2 weeks) or extended (8 weeks) to gauge the length of challenge necessary for remodeling. Additionally, platelet depletion allowed for the assessment of platelet relevance in PVAT leukocyte remodeling. Abdominal PVAT (aPVAT) and thoracic PVAT (tPVAT) were then isolated and leukocyte composition evaluated by flow cytometry. Compared to control, Western diet alone did not significantly impact PVAT leukocyte composition for either diet length. Platelet depletion, independent of diet, significantly disrupted PVAT leukocyte content with monocytes/macrophages most impacted. Furthermore, tPVAT appeared more sensitive to platelet depletion than aPVAT, providing novel evidence of platelet regulation of leukocyte composition within PVAT depots.

Rheumatoid arthritis (RA) is a chronic, invasive autoimmune disease characterized by symmetrical polyarthritis involving synovial inflammation. Epidemiological studies indicate that the incidence of RA continues to rise, yet the pathogenesis of this disease remains not fully understood. A significant infiltration of macrophages is observed in the synovium of RA patients. It can be inferred that macrophages likely play a crucial role in the onset and progression of RA.

This review aims to summarize the research progress on the mechanisms by which macrophages and their associated structures contribute to RA, as well as potential therapeutic approaches, aiming to provide new insights into the study of RA pathogenesis and its clinical treatment.

During the course of RA, besides the inherent roles of macrophages, these cells respond to microenvironmental changes such as pathogen invasion or tissue damage by undergoing polarization, pyroptosis, or forming macrophage extracellular traps (METs), all of which influence inflammatory responses and immune homeostasis, thereby mediating the occurrence and development of RA. Additionally, macrophages secrete exosomes, which participate in intercellular communication and signal transduction processes, thus contributing to the progression of RA. Therefore, it is critical to elucidate how macrophages and their related structures function in RA.

Rheumatoid arthritis (RA) is a chronic, invasive autoimmune disease characterized by symmetrical polyarthritis involving synovial inflammation. Epidemiological studies indicate that the incidence of RA continues to rise, yet the pathogenesis of this disease remains not fully understood. A significant infiltration of macrophages is observed in the synovium of RA patients. It can be inferred that macrophages likely play a crucial role in the onset and progression of RA.

This review aims to summarize the research progress on the mechanisms by which macrophages and their associated structures contribute to RA, as well as potential therapeutic approaches, aiming to provide new insights into the study of RA pathogenesis and its clinical treatment.

During the course of RA, besides the inherent roles of macrophages, these cells respond to microenvironmental changes such as pathogen invasion or tissue damage by undergoing polarization, pyroptosis, or forming macrophage extracellular traps (METs), all of which influence inflammatory responses and immune homeostasis, thereby mediating the occurrence and development of RA. Additionally, macrophages secrete exosomes, which participate in intercellular communication and signal transduction processes, thus contributing to the progression of RA. Therefore, it is critical to elucidate how macrophages and their related structures function in RA.

Kawasaki disease (KD) is a severe acute febrile illness and systemic vasculitis that causes coronary artery aneurysms in young children. Platelet hyperreactivity and an aberrant immune response are key indicators of KD; however, the mechanism by which hyperactive platelets contribute to inflammation and vasculopathy in KD remains unclear. A cytokine-mediated positive feedback loop between KD platelets and monocytes is identified. KD platelet-monocyte aggregates (MPAs) are mediated by an initial interaction of P-selectin (cluster of differentiation 62P, CD62p) and its glycoprotein ligand 1 (PSGL-1). This is followed by a coordinated interaction of platelet glycoprotein (GP)Ibα with monocyte CD11b. Monocyte-activated platelets initiate transforming growth factor (TGF)β1 release, which results in nuclear localization of nuclear factor kappaB in monocytes, therefore, driving the phenotypic conversion of classical monocytes (CD14+CD16-) into proinflammatory monocytes (CD14+CD16+). The platelet-activated monocytes release interleukin-1 and tissue necrotic factor-α, which promote further platelet activation. KD-induced inflammation and vasculopathy are prevented by inhibiting the components of this positive feedback loop. Notably, mice deficient in platelet TGFβ1 show less MPA and CD14+CD16+ monocytes, along with reduced inflammation and vasculopathy. These findings reveal that platelet-monocyte interactive proteins (CD62p/PSGL-1 and (GP)Ibα/CD11b) and cytokine mediators (platelet TGFβ1) are potential biomarkers and therapeutic targets for KD vasculopathy.

The interaction between renal intrinsic cells and macrophages plays a crucial role in the onset and progression of kidney diseases. In recent years, epigenetic mechanisms such as DNA methylation, histone modification, and non-coding RNA regulation have become essential windows for understanding these processes. This review focuses on how renal intrinsic cells (including tubular epithelial cells, podocytes, and endothelial cells), renal cancer cells, and mesenchymal stem cells influence the function and polarization status of macrophages through their own epigenetic alterations, and how the epigenetic regulation of macrophages themselves responds to kidney damage, thus participating in renal inflammation, fibrosis, and repair. Moreover, therapeutic studies targeting these epigenetic interaction mechanisms have found that the application of histone deacetylase inhibitors, histone methyltransferase inhibitors, various nanomaterials, and locked nucleic acids against non-coding RNA have positive effects on the treatment of multiple kidney diseases. This review summarizes the latest research advancements in these epigenetic regulatory mechanisms and therapies, providing a theoretical foundation for further elucidating the pathogenesis of kidney diseases and the development of novel therapeutic strategies.

Renal-clearable engineered nanoparticles are being explored for their potential to deliver therapeutic agents for kidney disease treatment. A fundamental understanding of how these nanoparticles accumulate in diseased kidneys at the cellular level is essential to enhance their effectiveness and minimize side effects on adjacent healthy tissues. Herein, we report that the accumulation of glutathione-coated, near-infrared emitting gold nanoparticles (GS-AuNPs) correlates strongly with the necrotic stages of injured proximal tubular cells. Using a rhabdomyolysis-induced acute kidney injury (AKI) mouse model, we observed that GS-AuNPs were significantly accumulated in the extracellular lumen of proximal tubular epithelial cells (PTECs) at advanced necrotic stage, where cellular debris and released intracellular contents impeded their clearance. In contrast, during early necrosis, GS-AuNPs were still cleared through the unobstructed lumen. Additionally, intracellular uptake of GS-AuNPs was significantly reduced across all necrotic stages. These findings underscore the need for new strategies to design nanoparticles that can effectively target and be taken up by the diseased tubular cells before extensive necrosis occurs; so that nanoparticle-mediated drug delivery for kidney disease treatment can be achieved with desired efficacy and precision.

We take a wide variety of antioxidants, including polyphenols, daily from our diet. They are generally considered to be beneficial for our health. However, the intrinsic function of antioxidants in biological systems remain unknown. On the other hand, antioxidants in general are sensitive to oxidation, generating their oxidized intermediates. Intriguingly, these intermediates are highly reactive to proteins. Although the specific cellular targets and response mechanism remain unclear, protein modification by oxidized antioxidants may represent the intrinsic "moonlight" function of antioxidants by taking on a secondary role beyond their traditional activity. This minireview summarizes recent findings on antioxidants, with a particular focus on the interactions of antioxidant-modified proteins with histones.

This study aimed to examine the impact of APS on acute kidney injury induced by rhabdomyolysis (RIAKI), exploring its association with macrophage M1 polarization and elucidating the underlying mechanisms.

C57BL/6J mice were randomly assigned to one of three groups: a normal control group, a RIAKI model group, and an APS treatment group. Techniques such as flow cytometry and immunofluorescence were employed to demonstrate that APS can inhibit the transition of renal macrophages to the M1 phenotype in RIAKI. Furthermore, the raw264.7 macrophage cell line was chosen and induced into the M1 phenotype to further examine the impact of APS on this model and elucidate the underlying mechanism.

Administration of APS led to a significant decrease in UREA levels by 25.2% and CREA levels by 60.9% within the model group. Also, APS exhibited an inhibitory effect on the infiltration of M1 macrophages and the cGAS-STING pathway in kidneys within the RIAKI, subsequently leading to decreased serum concentrations of IL-1β, IL-6 and TNF-α by 44.5%, 12.9%, and 10.3%, respectively, consistent with the results of in vitro experiments. Furthermore, APS exhibited an anti-apoptotic effect on MPC5 cells when co-cultured with M1 macrophages.

Astragalus polysaccharide (APS) potentially mitigated rhabdomyolysis-induced renal damage by impeding the M1 polarization of macrophages. This inherent mechanism might involve the suppression of the cGAS-STING pathway activation within macrophages. Furthermore, APS could endow protective effects on podocytes through the inhibition of apoptosis.

Renal transplantation and other conditions with transiently reduced blood flow is major cause of renal ischemia/reperfusion injury (RIRI), a therapeutic challenge clinically. This study investigated the role of liraglutide in ferroptosis-associated RIRI via macrophage extracellular traps (METs).

Animal model with RIRI was established in C57BL/6J mice. A total of 72 C57BL/6J mice were used with 8 mice per group. Primary tubular epithelium was co-culture with RAW264.7 under hypoxia/reoxygenation (H/R) condition to mimic in vitro. Liraglutide was administrated into mice and cells. Extracellular DNA, neutrophil elastase and myeloperoxidase in serum and supernatant of cell medium were collected for measuring METs. F4/80 and citH3 were labeled to show METs.

Liraglutide relieved RIRI and ferroptosis in vivo, and inhibited renal I/R-induced METs both in vivo and in vitro. F4/80 and citrullinated histone H3 (citH3) were highly co-localized after RIRI. Liraglutide attenuated the co-localization of citH3 and F4/80. Expressions of M2 markers were enhanced whereas these of M1 markers suppressed during liraglutide treatment in RIRI. Phosphorylation of signal transducer and activator of transcription (STAT)1, 3 and 6 were increased in RIRI mice and H/R-induced RAW264.7. However, liraglutide decreased phosphorylation of STAT1 and increased phosphorylation of STAT3 and STAT6. STAT3/6 inhibition reversed liraglutide-inhibited M1 polarization, extracellular traps and ferroptosis.

Liraglutide inhibited ferroptosis-induced renal dysfunction since it skewed macrophage polarization into M2 phenotype that interfered the formation of extracellular traps based on STAT3/6 pathway during RIRI. Liraglutide was proposed to be used for RIRI clinical treatment.

Hypertensive vascular disease (HVD) is a major health burden globally and is a comorbidity commonly associated with other metabolic diseases. Many factors are associated with HVD including obesity, diabetes, smoking, chronic kidney disease, and sterile inflammation. Increasing evidence points to neutrophils as an important component of the chronic inflammatory response in HVD. Neutrophils are abundant in the circulation and can respond rapidly upon stimulation to deploy an armament of antimicrobial effector functions. One of the outcomes of neutrophil activation is the generation of neutrophil extracellular traps (NETs), a regulated extrusion of chromatin and proteases. Although neutrophils and NETs are well described as components of the innate immune response to infection, recent evidence implicates them in HVD. Endothelial cell activation can trigger neutrophil adhesion, activation, and production of NETs promoting vascular dysfunction, vessel remodelling, and loss of resistance. The regulated release of NETs can be controlled by the pore-forming activities of distinct cell death pathways. The best characterized pathways in this context are apoptosis, pyroptosis, and necroptosis. In this review, we discuss how inflammatory cell death signalling and NET formation contribute to hypertensive disease. We also examine novel therapeutic approaches to limit NET production and their future potential as therapeutic drugs for cardiovascular disorders.

Excessive formation of macrophage extracellular trap (MET) has been implicated in several autoimmune disease pathogeneses; however, its impact on type 1 diabetes (T1D) and related mechanisms remains enigmatic. We demonstrated the pivotal role of peptidyl arginine deiminase 4 (PAD4) in driving profuse MET formation and macrophage M1 polarization in intestinal inflammation in NOD mice. Genetic knockout of PAD4 or adoptive transfer of METs altered the proportion of proinflammatory T cells in the intestine, subsequently influencing their migration to the pancreas. Combining RNA sequencing and CUT&Tag analysis, we found activated PAD4 transcriptionally regulated CXCL10 expression. This study comprehensively investigated how excessive PAD4-mediated MET formation in the colon increases the aggravation of intestinal inflammation and proinflammatory T-cell migration and finally is involved in T1D progression, suggesting that inhibition of MET formation may be a potential therapeutic target in T1D.

Ferroptosis is a newly identified form of programmed cell death that is connected to iron-dependent lipid peroxidization. It involves a variety of physiological processes involving iron metabolism, lipid metabolism, oxidative stress, and biosynthesis of nicotinamide adenine dinucleotide phosphate, glutathione, and coenzyme Q10. So far, it has been discovered to contribute to the pathological process of many diseases, such as myocardial infarction, acute kidney injury, atherosclerosis, and so on. Macrophages are innate immune system cells that regulate metabolism, phagocytize pathogens and dead cells, mediate inflammatory reactions, promote tissue repair, etc. Emerging evidence shows strong associations between macrophages and ferroptosis, which can provide us with a deeper comprehension of the pathological process of diseases and new targets for the treatments. In this review, we summarized the crosstalk between macrophages and ferroptosis and anatomized the application of this association in disease treatments, both non-neoplastic and neoplastic diseases. In addition, we have also addressed problems that remain to be investigated, in the hope of inspiring novel therapeutic strategies for diseases.

Crystalline material can cause a multitude of acute and chronic inflammatory diseases, such as gouty arthritis, silicosis, kidney disease, and atherosclerosis. Crystals of various types are thought to cause similar inflammatory responses, including the release of proinflammatory mediators and formation of neutrophil extracellular traps (NETs), processes that further promote necroinflammation and tissue damage. It has become apparent that the intensity of inflammation and the related mechanisms of NET formation and neutrophil death in crystal-associated diseases can vary depending on the crystal type, amount, and site of deposition. This review details new mechanistic insights into crystal biology, highlights the differential effects of various crystals on neutrophils and extracellular trap (ET) formation, and discusses treatment strategies and potential future approaches for crystal-associated disorders.

Accumulating evidence has substantiated the potential of ambient particulate matter (PM) to elicit detrimental health consequences in the respiratory system, notably airway inflammation. Macrophages, a pivotal component of the innate immune system, assume a crucial function in responding to exogenous agents. However, the roles and detailed mechanisms in regulating PM-induced airway inflammation remain unclear. The current study revealed that PM had the ability to stimulate the formation of macrophage extracellular traps (METs) both in vitro and in vivo. This effect was dependent on peptidylarginine deiminase type 4 (PAD4)-mediated histone citrullination. Additionally, reactive oxygen species were involved in the formation of PM-induced METs, in parallel with PAD4. Genetic deletion of PAD4 in macrophages resulted in an up-regulation of inflammatory cytokine expression. Moreover, mice with PAD4-specific knockout in myeloid cells exhibited exacerbated PM-induced airway inflammation. Mechanistically, inhibition of METs suppressed the phagocytic ability in macrophages, leading to airway epithelial injuries and an aggravated PM-induced airway inflammation. The present study demonstrates that METs play a crucial role in promoting the phagocytosis and clearance of PM by macrophages, thereby suppressing airway inflammation. Furthermore, it suggests that activation of METs may represent a novel therapeutic strategy for PM-related airway disorders.

Crush syndrome, which frequently occurs in earthquake disasters, often leads to rhabdomyolysis induced acute kidney injury (RIAKI). Recent findings indicate that systemic inflammatory response syndrome (SIRS) exacerbates muscle collapse, contributing to RIAKI. The purpose of this study is to investigate the involvement of multiple site inflammation, including intraperitoneal, in crush syndrome. In a mouse model of RIAKI, elevated levels of inflammatory mediators such as TNFα, IL-6, myoglobin, and dsDNA were observed in serum and the peritoneal cavity, peaking earlier in the intraperitoneal cavity than in serum or urine. Our previously developed novel peptide inhibiting leukocyte extracellular traps was administered intraperitoneally and blocked all of these mediators in the intraperitoneal cavity and serum, ameliorating muscle damage and consequent RIAKI. Although further studies are needed to determine whether intraperitoneal inflammation associated with muscle collapse can lead to systemic inflammation, resulting in more severe and prolonged muscle damage and renal injury, early suppression of multiple site inflammation, including intraperitoneal, might be an effective therapeutic target.

Monocytes and macrophages play an indispensable role in maintaining intestinal homeostasis and modulating mucosal immune responses in inflammatory bowel disease (IBD). Although numerous studies have described macrophage properties in IBD, the underlying mechanisms whereby the monocyte-macrophage lineage modulates intestinal homeostasis during gut inflammation remain elusive.

In this review, we decipher the cellular and molecular mechanisms governing the generation of intestinal mucosal macrophages and fill the knowledge gap in understanding the origin, maturation, classification, and functions of mucosal macrophages in intestinal niches, particularly the phagocytosis and bactericidal effects involved in the elimination of cell debris and pathogens. We delineate macrophage-mediated immunoregulation in the context of producing pro-inflammatory and anti-inflammatory cytokines, chemokines, toxic mediators, and macrophage extracellular traps (METs), and participating in the modulation of epithelial cell proliferation, angiogenesis, and fibrosis in the intestine and its accessory tissues. Moreover, we emphasize that the maturation of intestinal macrophages is arrested at immature stage during IBD, and the deficiency of MCPIP1 involves in the process via ATF3-AP1S2 signature. In addition, we confirmed the origin potential of IL-1B+ macrophages and defined C1QB+ macrophages as mature macrophages. The interaction crosstalk between the intestine and the mesentery has been described in this review, and the expression of mesentery-derived SAA2 is upregulated during IBD, which contributes to immunoregulation of macrophage. Moreover, we also highlight IBD-related susceptibility genes (e.g., RUNX3, IL21R, GTF2I, and LILRB3) associated with the maturation and functions of macrophage, which provide promising therapeutic opportunities for treating human IBD.

In summary, this review provides a comprehensive, comprehensive, in-depth and novel description of the characteristics and functions of macrophages in IBD, and highlights the important role of macrophages in the molecular and cellular process during IBD.

Extracellular traps (ETs) are a specialized form of innate immune defense in which leukocytes release ETs composed of chromatin and active proteins to eliminate pathogenic microorganisms. In addition to the anti-infection effect of ETs, researchers have also discovered their involvement in the pathogenesis of inflammatory disease, tumors, autoimmune disease, and allergic disease. Asthma is a chronic airway inflammatory disease involving multiple immune cells. The increased level of ETs in asthma patients suggests that ETs play an important role in the pathogenesis of asthma. Here we review the research work on the formation mechanism, roles, and therapeutic strategies of ETs released by neutrophils, eosinophils, and macrophages in asthma.

Macrophages possess a diverse range of well-defined capabilities and roles as phagocytes, encompassing the regulation of inflammation, facilitation of wound healing, maintenance of tissue homeostasis, and serving as a crucial element in the innate immune response against microbial pathogens. The emergence of extracellular traps is a novel strategy of defense that has been observed in several types of innate immune cells. In response to infection, macrophages are stimulated and produce macrophage extracellular traps (METs), which take the form of net-like structures, filled with strands of DNA and adorned with histones and other cellular proteins. METs not only capture and eliminate microorganisms but also play a role in the development of certain diseases such as inflammation and autoimmune disorders. The primary objective of this study is to examine the latest advancements in METs for tackling bacterial infections. We also delve into the current knowledge and tactics utilized by bacteria to elude or endure the effects of METs. Through this investigation, we hope to shed light on the intricate interactions between bacteria and the host's immune system, particularly in the context of microbicidal effector mechanisms of METs. The continued exploration of METs and their impact on host defense against various pathogens opens up new avenues for understanding and potentially manipulating the immune system's response to infections.

Mean platelet volume (MPV), which is regarded as a marker of thrombocyte function and activation, is related to increased morbidity and mortality. In critically ill patients, the ratio of MPV to platelets can independently predict adverse outcomes. This study aimed to investigate the prognostic value of the mean platelet volume/platelet count ratio (MPR) for mortality in children with acute kidney injury (AKI).

In this retrospective study, patients hospitalized in the pediatric intensive care unit (PICU) between March 2020 and June 2022 were evaluated. Patients between 1 month and 18 years of age with AKI were enrolled. Clinical and laboratory data were compared between survivors and non-survivors. The MPR ratio was calculated on the first and third days of admission to the intensive care unit. A multiple logistic regression analysis was used to determine the association between MPR and mortality. ROC curves were used for the prediction performance of the logistic regression models and cut-off values of the thrombocyte indices.

Sixty-three children with AKI were included in the study. The total mortality rate was 34.9% (n=22). MPR ratios were significantly higher in the non-survivors at admission (p=0.042) and at the 72nd hour (p=0.003). In the multiple logistic regression analysis, thrombocyte counts and MPR72h ratio were found to be independent risk parameters for adverse outcomes in children with AKI.

MPR is an inexpensive and practical marker that may predict the outcome of children with AKI.

Acute kidney injury (AKI) is a major worldwide health concern that currently lacks effective medical treatments. PSMP is a damage-induced chemotactic cytokine that acts as a ligand of CCR2 and has an unknown role in AKI. We have observed a significant increase in PSMP levels in the renal tissue, urine, and plasma of patients with AKI. PSMP deficiency improved kidney function and decreased tubular damage and inflammation in AKI mouse models induced by kidney ischemia-reperfusion injury, glycerol, and cisplatin. Single-cell RNA sequencing analysis revealed that Ly6Chi or F4/80lo infiltrated macrophages (IMs) were a major group of proinflammatory macrophages with strong CCR2 expression in AKI. We observed that PSMP deficiency decreased CCR2+Ly6Chi or F4/80lo IMs and inhibited M1 polarization in the AKI mouse model. Moreover, overexpressed human PSMP in the mouse kidney could reverse the attenuation of kidney injury in a CCR2-dependent manner, and this effect could be achieved without CCL2 involvement. Extracellular PSMP played a crucial role, and treatment with a PSMP-neutralizing antibody significantly reduced kidney injury in vivo. Therefore, PSMP might be a therapeutic target for AKI, and its antibody is a promising therapeutic drug for the treatment of AKI.

Mechanistic studies showed that morphine may impair the antiplatelet effect of P2Y12 inhibitors. However, Several clinical studies with cardiovascular events as an outcome are contradictory, and the broader impact of this drug interaction on additional organ systems remains uncertain. With multisource data, this study sought to determine the effects of morphine interaction with P2Y12 inhibitors on major adverse outcomes comprehensively, and identify the warning indicators.

Interaction signals were sought in 187,919 safety reports from the FDA Adverse Event Reporting System (FAERS) database, utilizing reporting odds ratios (repOR). In a cohort of 5240 acute coronary syndrome patients, the analyses were validated, and the biological effects of warning indicators were further studied with Mendelian randomization and mediation analysis.

Potential risk of renal system adverse events in patients cotreated with morphine is significantly higher in FAERS (repOR 4.83, 95% CI 4.42-5.28, false discovery rate adjusted-P =3.55*10-209). The analysis of in-house patient cohorts validated these results with an increased risk of acute kidney injury (adjusted OR: 1.65; 95% CI: 1.20 to 2.26), and we also found a risk of myocardial infarction in patients treated with morphine (adjusted OR: 1.55; 95% CI: 1.14 to 2.11). The Morphine group exhibited diminished Plateletcrit (PCT) levels post-surgery and lower PCT levels were associated with an increased risk of AKI.

The administration of morphine in patients treated with P2Y12 receptor inhibitors should be carefully evaluated. PCT may serve as a potential warning indicator for morphine-related renal injury.

Circulated histones play a crucial role in the pathogenesis of infectious diseases and severe trauma, and it is one of the potential molecular targets for therapeutics. Recently, we reported that histone is one of the causative agents for urinary L-FABP increase. However, the mechanism is still unclear, especially in severe cases. We further investigated the mechanism of urinary L-FABP increase using a more severe mouse model with histone-induced kidney injury. This study also aims to evaluate the therapeutic responsiveness of urinary L-FABP as a preliminary study.

Human L-FABP chromosomal transgenic mice were administrated 30 mg/kg histone from a tail vein with a single dose. We also performed a comparative study in LPS administration model. For the evaluation of the therapeutic responsiveness of urinary L-FABP, we used heparin and rolipram.

The histological change with cast formation as a characteristic of the models was observed in proximal tubules. Urinary L-FABP levels were significantly elevated and these levels tended to be higher in those with more cast formation. Heparin and rolipram had the ameliorative effect of the cast formation induced by histone and urinary L-FABP levels significantly decreased.

Histone is one of the causative agents for the increase of urinary L-FABP at an early stage of AKI. In addition, it suggested that urinary L-FABP may be useful as a subclinical AKI marker reflecting kidney damage induced by histone. Furthermore, urinary L-FABP reflected the degree of the damage after the administration of therapeutic agents such as heparin and PDE4 inhibitor.

Neutrophil extracellular traps (NETs) are implicated in the pathogenesis of abdominal aortic aneurysm (AAA), located in adventitia and intraluminal thrombus. We compared the therapeutic potential of targeting upstream or downstream effector molecules of NET formation in 2 murine AAA models based on angiotensin II or peri-adventitial elastase application. In both models, NETs were detected in formed aneurysms at treatment start. Although NET inhibitors failed in the elastase model, they prevented progression of angiotensin II-induced aneurysms with thrombus, which resembles established human disease (including thrombus development). Blockade of upstream NET mediators was more effective than interference with downstream NET molecules.

Reactive astrocytes (RAs) produce chondroitin sulfate proteoglycans (CSPGs) in large quantities after spinal cord injury (SCI) and inhibit axon regeneration through the Rho-associated protein kinase (ROCK) pathway. However, the mechanism of producing CSPGs by RAs and their roles in other aspects are often overlooked. In recent years, novel generation mechanisms and functions of CSPGs have gradually emerged. Extracellular traps (ETs), a new recently discovered phenomenon in SCI, can promote secondary injury. ETs are released by neutrophils and microglia, which activate astrocytes to produce CSPGs after SCI. CSPGs inhibit axon regeneration and play an important role in regulating inflammation as well as cell migration and differentiation; some of these regulations are beneficial. The current review summarized the process of ET-activated RAs to generate CSPGs at the cellular signaling pathway level. Moreover, the roles of CSPGs in inhibiting axon regeneration, regulating inflammation, and regulating cell migration and differentiation were discussed. Finally, based on the above process, novel potential therapeutic targets were proposed to eliminate the adverse effects of CSPGs.

Sepsis-induced acute kidney injury (SAKI) is a life-threatening condition with complex pathophysiology, often exacerbated by immune cell dysregulation. In this comprehensive study, we leverage publicly available single-cell RNA sequencing (scRNA-seq) datasets to unravel the intricate immune responses occurring during SAKI, shedding light on macrophages as critical players. Specifically, we identify Saa3, a gene primarily expressed in macrophages, as a potent pro-inflammatory cytokine in SAKI. Saa3hi Ccl2hi monocyte-derived infiltrated macrophages (IMs) emerge as a central effector subset, fostering inflammation, and directly engaging with renal cells. Our findings suggest that Saa3 may be a promising predictive marker of SAKI, although further exploration of human homologs is warranted.

Clinical risk prediction with electronic health records (EHR) using machine learning has attracted lots of attentions in recent years, where one of the key challenges is how to protect data privacy. Federated learning (FL) provides a promising framework for building predictive models by leveraging the data from multiple institutions without sharing them. However, data distribution drift across different institutions greatly impacts the performance of FL. In this paper, an adaptive FL framework was proposed to address this challenge. Our framework separated the input features into stable, domain-specific, and conditional-irrelevant parts according to their relationships to clinical outcomes. We evaluate this framework on the tasks of predicting the onset risk of sepsis and acute kidney injury (AKI) for patients in the intensive care unit (ICU) from multiple clinical institutions. The results showed that our framework can achieve better prediction performance compared with existing FL baselines and provide reasonable feature interpretations.